JPH02105826A - Preparation of hydrophilic polymer particle - Google Patents

Abstract

PURPOSE:To prepare the title fine particles with a controlled particle size substantially in the absence of any org. solvent by forming small bubbles enclosed in a lipid membrane in an aq. soln. contg. a polymer precursor and polymerizing selectively said precursor in the small bubbles. CONSTITUTION:Pref. 0.2-100mmol of a lipid (e.g., dipalmitoylphosphatidylchloine) based on the following aq. soln. is added to an aq. soln. contg. a polymer precursor (e.g., acrylamide or N,N'-methylenebisacrylamide) and dispersed therein by ultrasonic treatment to form small bubbles enclosed in the lipid membrane in said aq. soln. An additive for preventing polymerization outside the small bubbles (e.g., potassium ferrocyanide) is added thereto and the polymer precursor in the small bubbles is selectively polymerized pref. by irradiation with a radiation.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing polymer granules.

(Prior art and its problems) Conventionally, methods for obtaining granular polymer materials include methods for converting polymer materials synthesized into shapes other than granules into granules by means such as pulverization, or methods for obtaining granular polymer materials from the beginning. There is a method of producing polymers in granular form. Both methods are practiced industrially, but the latter is particularly characterized in that the particle size and shape of the resulting polymer material can be made uniform.

As the latter method of forming a polymer into particles, emulsion polymerization, suspension polymerization, and seed polymerization as variations thereof are known.

These methods have in common that two immiscible phases are made to coexist and a polymer is produced in one of the discontinuous phases. In these methods, the particle size of the polymer particles produced is determined by the volume ratio of the two phases and the width of the two-phase interface, and these are determined by the respective volumes of the two phases, viscosity, stirring conditions of the reactive species, and the interface. It is sensitively affected by the concentration of additives such as activators.

Furthermore, since the interface between the two phases has positive energy, the selection of the surfactant is particularly important when producing a polymer material in the form of microscopic particles with a diameter of about 1 μm. In particular, when making granules of hydrophilic polymers, it is necessary to maintain a stable W2O type reversed phase dispersion state, which requires a large amount of organic solvent and requires 0.1
There is a problem in that it is difficult to manufacture granular materials with a size of μm or less.

Accordingly, one of the objects of the present invention is to provide a manufacturing method in which the particle size of polymer particles is not easily influenced by the reaction conditions during polymer production, thereby facilitating particle size control.

Another object of the present invention is to provide a method for easily preparing polymer particles having a particle size of 1 μm or less.

(Means for solving problems) The above objects are achieved by the present invention as described below.

That is, the present invention comprises a step of forming a vesicle closed by a lipid membrane in an aqueous solution containing a polymer precursor, and a step of selectively polymerizing the polymer precursor within the vesicle. This is a method for producing a hydrophilic polymer granule.

(Function) According to the structure of the present invention, the particle size of the produced particles can be controlled without being affected by the reaction conditions during polymer production, and polymer particles having a particle size of 1 μm or less can be easily provided.

(Preferred Embodiments) Next, the present invention will be explained in more detail with reference to preferred embodiments.

The method for producing a polymer granule of the present invention includes (1) sealing a polymer precursor in microvesicles closed with a lipid membrane; and (2) converting the polymer precursor into a polymer in the sealed space. It is characterized by the process of converting.

The lipid membrane used in the present invention is a two-dimensional structure formed by association of lipids through intermolecular forces and hydrophobic interactions. The lipid used in the present invention is known as an amphipathic substance that can form such a two-dimensional structure, and any known lipid can be used, but specific examples include dipalmitoylphosphatidylcholine, Dialkyl compounds such as simyristoylphosphatidylserine, distearyldimethylammonium puromite, C)+3 (
CH2) So-C@-N-CIF@/-0(C1(
Typical examples include compounds having a hydrophobic group having a rigid part and one or two hydrophilic groups such as 4-N''(CH3)3Br-. Substances in which some or all of the hydrogen atoms in the chain are replaced with fluorine are also preferably used.

The above substances can be used alone, or two or more types can be used in combination. Furthermore, neutral lipids such as various higher fatty acids or their esters, amide derivatives, and cholesterol may be mixed to the extent that a two-dimensional structure can be formed in an aqueous solution. When these lipids are dispersed in an aqueous solution containing a polymeric precursor using an appropriate means, vesicles are formed and a portion of the aqueous solution is taken up inside.

The amount of lipid added to the aqueous solution is 0.2 as total lipid.
A concentration range from mM (millimol) to 100 mM is preferred. If an amount of lipid exceeding the above range is used, it becomes difficult to disperse the entire amount of lipid in an apparently uniform manner in an aqueous solution. On the other hand, if the amount is less than the above range, the proportion of the aqueous solution retained inside the lipid vesicles will be small, resulting in a small amount of polymer particles finally obtained, which is not practical.

The size of the aqueous phase inside the lipid vesicle can be adjusted within the range of 3 μm to 10 nm depending on the lipid used, dispersion means, etc.

The polymer precursors used in the present invention include monomers that can form polymers, oligomers that have reactive activity,
Any polymer that has reactive activity and can be substantially dissolved in an aqueous solution can be used. In particular, if a polymer precursor is used in which the polymer generated in the polymerization process is insoluble in water, the polymer that remains stable in water even after the fat R film is removed from the resulting polymer granules. This is preferred because molecular granules can be obtained.

As mentioned above, the precursors that produce water-insoluble polymers include:
Among monomers and oligomers, the solubility in water becomes particularly low when polymerized, and in the case of polymers with reaction activity, the solubility in water of the new polymer produced as a result of the reaction is particularly low. You can use something like this. Further, the polymerization step in which a polymer having a crosslinked structure is formed in the polymerization step described above is also an example of producing an insoluble polymer.

Various methods have been known for forming vesicles by dispersing lipids in an aqueous solution, and it is possible to select an appropriate method among them to form vesicles of the desired size. I can do it. Dispersion using ultrasonic waves is particularly effective for obtaining fine polymer particles. On the other hand, for the purpose of obtaining relatively large granules, an effective method is to dissolve the lipid in an organic solvent that is insoluble in water, add this to an aqueous solution of a polymer precursor, and then evaporate and remove the organic solvent.

After lipid vesicles are formed, a polymerization reaction retardant or inhibitor is added to the outer aqueous phase in order to prevent polymerization of the polymer @ precursor substance present in the outer aqueous phase of the vesicle. .

These additives must, of course, not migrate through the interface of the lipid vesicles into the inner aqueous phase. The above additives that can be used must be selected depending on the type of polymer precursor used. For example, when the polymerization reaction in the polymerization step is radical polymerization, hydroquinone sulfonic acid is used as an additive. Sodium, sodium ascorbate, 2,2,5.5-tetramethylpyrrolidine-1
-Sodium oxyl-3-carboxylate, 2.2,5.
Sodium 5-tetramethylpyroline-1-oxyl-3-carbonate, sodium 2.2,5.5-tetramethylpyrroline-N-oxide-3-carboxylate, thionine, iron chloride, copper chloride, zinc chloride, ferro A water-soluble substance having a radical reaction inhibiting effect, such as potassium cyanide, can be used.

Preferably, the additives are present in the outer aqueous phase of the lipid vesicles in a concentration range of 1mM to 3M. Although it depends on the types of additives and polymer precursors used, in general, concentrations lower than this are not sufficient to stop the polymerization reaction outside of lipid vesicles, and concentrations exceeding this are generally used. This is not preferable since it may impair the stability of lipid vesicles once formed.

When the above-mentioned additives for suppressing polymerization reactions are added to the outer aqueous phase of lipid vesicles, depending on the conditions, aggregation or fusion of the lipid vesicles may occur, or part of the additive may be absorbed into the lipid membrane of the vesicles. It may pass through and connect to the inner water phase. Such a phenomenon may cause the particle size of the produced polymer particles to become non-uniform, or
It is necessary to prevent this because it inhibits the generation of particulate matter itself.

If a material exhibiting a gel-liquid crystal phase transition is used as the lipid, the above problems can be partially resolved. That is, the lipid cell formation step is performed as described above at a temperature above the phase transition temperature of the lipid (i.e., when the lipid is in a liquid crystal state with fluidity), and then, at a temperature below the phase transition temperature of the lipid (i.e., when the lipid is in a liquid crystal state with fluidity). If an additive that suppresses the polymerization reaction (in a gel state that has lost its molecular weight) is added to the aqueous phase outside the vesicles, fusion of the vesicles and permeation of the additive through the lipid membrane can be prevented. In this case, the temperature should be maintained below the phase transition temperature of the lipid even in the next polymerization step.

After the vesicles as described above are stably formed, the polymeric 11i'r precursor is polymerized by means depending on the @ precursor used. As a means for this, it is possible to use a substance that has a catalytic effect to initiate the polymerization reaction, but
More preferably, irradiation with radiation such as visible light, ultraviolet rays, X-rays, and γ-rays can be used. When these radiations are used, a compound having a sensitizing effect to radiation may be co-existed with the polymer precursor in order to promote the polymerization reaction.

The polymer precursor within the lipid vesicles is polymerized by the polymerization reaction, and polymer particles are obtained in a state dispersed in an aqueous solution. If the lipid remains around the particles, the dispersion state is stable. If it is necessary to remove lipids, it can be done by adding a surfactant to the resulting dispersion to destroy the idioplasmic membrane and washing the particles.

The method for producing particulate polymers described above is similar to reverse-phase suspension polymerization and reverse-phase emulsion polymerization in that an amphiphilic substance is used to disperse an aqueous phase containing a polymer precursor. However, a feature of this method is that both of the two layers that are in contact with each other via the amphiphilic substance layer are aqueous phases. Once formed, such an amphiphilic material layer, that is, a lipid membrane, is stable and is not easily destroyed even by operations such as polymerization of a polymer precursor, and therefore, it is difficult to produce the polymer granules of the present invention. It effectively contributes to the purpose of regulating the particle size of polymers in the method.

In addition, in the general suspension polymerization method and emulsion polymerization method, the surfactant molecules used are rapidly exchanged between the state existing at the interface and the state dissolved in the two liquid phases, and the dispersion system of the present invention is In comparison, it is more sensitive to environmental conditions, so it is difficult to obtain the same effects as the present invention.

(Example) Hereinafter, the method for producing a hydrophilic polymer granule of the present invention will be explained using specific examples.

Example 1 Hydroxyethyl acrylate 4g, acrylamide 16
g and 1.8 g of sodium chloride are dissolved in 200 mu of water. 6 g of egg yolk lecithin is dissolved in 20 ml of chloroform, and the chloroform is removed under reduced pressure in a stainless steel container with a capacity of 500 mR while rotating the container. The above-mentioned aqueous solution is placed in this container, and treated with a probe-type ultrasonic oscillator (28 KHz, 2001) for 20 minutes while being externally cooled to 5°C. 3. The obtained aqueous solution. At OOOrpm 2
Centrifuge for 0 min to remove the precipitate, freeze in a dry ice/acetone bath, then thaw in a 15°C water bath. This liquid is first filtered under pressure using a polycarbonate membrane with a pore size of 2.0 μm, and then filtered under pressure using a polycarbonate membrane with a pore size of 0.4 μm to form lipid vesicles. 1 in this filtrate
The same volume of 8% sodium ascorbate aqueous solution is added, maintained at 20°C, and irradiated with gamma rays from a C66o source at 1.2 x 106 R,/hr for 8 hours under a nitrogen atmosphere. Next, add 5% of the liquid volume of Triton X100 (Rohm and Haas), dilute with 2 volumes of water,
By centrifuging at 20,000 rpa+ for 1 hour, polymer fine particles precipitated in the form of a translucent paste were obtained. When the ice crystals were dispersed in pure water and the particle size was measured by a light scattering method, the average particle size was 420 nm.

Example 2 Acrylic acid and droxyethyl 4g% N, N-methylenebisacrylamide 15g, acrylamide 20g, potassium chloride 1.8g and riboflavin 70mg were added to 200 g of water.
Add to m1 and stir. Thereafter, lipid vesicles are formed in the same manner as in Example 1.

The same volume of 18% by weight sodium ascorbate aqueous solution is added to the dissolved aqueous solution, and the mixture is irradiated with white fluorescent lamps (4 6W lamps) from a distance of 5 cm for 60 minutes in an atmosphere while maintaining the temperature at 10°C. Thereafter, the same treatment as in Example 1 was performed to obtain particles with an average particle size of 350 nm.

Example 3 Polymer particles with an average particle size of 2!0 μm were obtained by carrying out the same operation as in Example 1, except that the pore size of the polycarbonate membrane used for pressure filtration at 2 degrees H was set to 0.2 μm.

Example 4 10 g of acrylamide, 2.5 g of N,N-methylenebisacrylamide and 0.9 g of sodium chloride were added to 100 g of water.
Dissolve in mJl. 2.6 g of dipalmitoylphosphatidylcholine and 0.2 g of cholesterol were mixed with 2.2 g of ethanol.
Dissolve in 0 mL and dry in a glass container with a gentle stream of air. The aqueous solution was added to this container, heated to 50°C, and heated to a probe type ultrasonic oscillator (28 KHz, 12
0w) for 30 minutes. The resulting aqueous solution was heated to 5°C.
3. Centrifuge at OOOrpm for 20 minutes to remove the precipitate. This liquid is cooled to 5° C. and mixed with the same volume of a 16% by weight aqueous solution of potassium ferrocyanide.

The solution was cooled to 5°C and stirred, and γ was obtained under the same conditions as in Example 1.
Polymer particles with an average particle size of 18 nm were obtained by irradiation with the beam.

Example 5 0.2 g of sodium acrylate is dissolved in 2 mJZ of water. Dimyristoylphosphatidylglycerol 7mg,
36 mg of simiristoylphosphatidylcholine and 24 mg of cholesterol are dissolved in 7 mj2 of diethyl ether, and the above aqueous solution is added and subjected to ultrasonication to form an emulsion. The ether is distilled off under reduced pressure. If the liquid loses fluidity during distillation, shake the liquid and continue distilling.

The obtained liquid is cooled to 4° C., and the same volume of a 16 fi% potassium ferrocyanide aqueous solution is added. This solution was kept at 4°C and exposed to 28106 R/hr of gamma rays (co") under a nitrogen atmosphere.
) was irradiated for 2 hours to obtain particles with an average diameter of 0.58 μm.

Example 6 2 g of N-vinylpyrrolidone, 4 g of acrylamide, 0.3 g of ethylene glycol diacrylate and 0.6 g of sodium chloride are dissolved in 70 mρ of water. egg yolk lecithin 4
5 mg is dissolved in 35 mff1 of diethyl ether. The above aqueous solution is heated to 35°C, and the above ether solution is slowly injected while the pressure is slightly reduced. The same volume of 18% by weight sodium ascorbate aqueous solution was added to this aqueous solution, and γ-ray irradiation was performed in the same manner as in Example 1 to obtain an average particle size of 0.2.
Particles of μm were obtained.

(Effects) As explained above, according to the method of the present invention, <1) the particle size of the hydrophilic polymer particles can be controlled in the lipid vesicle formation step independently of the reaction conditions of the polymer production step; I can do it.

(2) It is possible to produce minute hydrophilic polymer particles of 0.1 μm or less.

(3) Hydrophilic polymer granules can be produced in an aqueous solution system without using much battering machine solvent.

Effects not found in conventional methods were obtained in these respects.

[Brief explanation of drawings]

Figure 1 is a schematic diagram showing a state in which vesicles made of lipid membranes are formed in an aqueous solution in which a polymer precursor is dispersed;
The figure is a schematic diagram showing a state in which a polymer precursor is polymerized in the intravesicular aqueous phase. 1: Aqueous solution in which a polymer precursor and polymerization reaction inhibitor are dispersed 2: Lipid membrane 3: Aqueous solution in which a polymer precursor is dispersed 4: Hydrophilic polymer granules Figure 1

Claims (3)

[Claims] (1) It is characterized by comprising a step of forming a vesicle closed by a lipid membrane in an aqueous solution containing a polymer precursor, and a step of selectively polymerizing the polymer precursor within the vesicle. A method for producing a hydrophilic polymer granule. (2) The method for producing hydrophilic polymer granules according to claim 1, wherein an additive for suppressing polymerization reaction is present outside the vesicles. (3) The method for producing hydrophilic polymer particles according to claims 1 and 2, wherein the polymerization step involves irradiation with radiation.